We are investigating the intrinsic reactivity of beta-lactams for understanding the mechanisms of action and inactivation of beta-lactamases and penicillin-binding proteins. Ab initio quantum mechanical calculations using a polarizable continuum model to estimate solvation effects have been utilized to analyze the hydrolysis and methanolysis of selected beta-lactams and simple amides. The roles of four-membered ring strain, reduced amide resonance, substituent and ring fusion effects on hydrolysis and methanol-mediated hydrolysis of these compounds have been studied by reconstructing the corresponding reaction pathways in gas and solution. Insights into this reactivity could prove very useful in the design of novel potent antimicrobials. The Computer Graphics Laboratory facilities has been used for visualization of the molecules.